The focus of this proposal is development of solid phase technology for the synthesis of combinatorial libraries of bicyclams. Some members of this class have been showed to be very potent inhibitors of HIV (human immunodeficiency virus) multiplication with very low cellular toxicity. By lead optimization, compounds with enhanced potency and improved bioavailability may be discovered in which toxic side effects of metal complexation associated with this class of compound may be alleviated. Metal affinity will be determined by novel high throughput screens and anti-HIV activity will be determined in cellular assays. PROPOSED COMMERCIAL APPLICATIONS: AIDS is a major drain on the economy of developing countries. Current therapeutic approaches lead to resistant virus. A different modality of action suggests that biclam may be less likely to develop resistance. Optimization of potency while minimizing side effects should lead to a novel and commercially successfully drug.